Schizophrenia and Alzheimer's disease are major public health problems. The problems associated with these diseases are compounded by the lack of clinically useful, objective methods of diagnosis. This diagnostic deficiency reflects a lack of understanding of the pathophysiology involved.
Many diseases of the central nervous system (CNS), such as Alzheimer's disease and schizophrenia, have few objective physical or biochemical markers useful for diagnostic purposes in the living patient. Alzheimer's disease, the most common form of dementia affecting up to 15% of people over 65 years of age (Pfeffer et al., 1987 Am. J. Epidemiol, 125:420) can only be presumptively diagnosed by pathological examination of brain tissue in conjunction with a clinical history of dementia (Khachaturian 1985 Arch. Neurol., 42:1097). In the diagnosis of schizophrenia, the clinician is limited to aberrations of behavior. No generally accepted laboratory markers for either of these two diseases of the CNS have been found that would allow for diagnosis in a living subject. Cerebrospinal fluid (CSF), which can be obtained by lumbar puncture, provides a source of proteins which may, in part, reflect abnormal CNS metabolism.
In a search for protein variations in Alzheimer's disease and schizophrenia, high resolution two-dimensional protein electrophoresis (O'Farrell, 1975 J. Biol. Chem., 250:4007; Hochstrasser et al., 1988 Anal. Biochem., 173:424) was employed combined with silver staining (Merril and Harrington, 1984 Clin. Chem., 30:1938) and computer-assisted image analysis (Olson and Miller, 1988 Anal. Biochem., 169:49). These techniques allowed screening of an average of 1,000 proteins per gel containing 40 .mu.l of CSF or 10 .mu.g of protein. These methods of analysis provided the ability to detect changes in a protein's charge, mass, and/or concentration which might be the result of mutational effects, post-translational modifications, or variations in protein metabolism.
One group of proteins associated with such disorders are proteins produced in acute-phase reactions. This family of protein's expression can be dramatically increased by a variety of insults including infectious diseases, leukemia, Down's Syndrome, and others. One such protein, haptoglobin, is known to increase in the plasma in a number of acute and chronic inflammations (Koy, 1974 Acute-Phase Reactions, In: Allison, A. C. (ed). Structure and function of plasma proteins. Plenum Press, New York, pp. 73-133). Another acute phase protein, fibrinogen, is synthesized in the liver and is increased concentration in plasma after infection or injury. Two proteins, proteins 127 and 128 which have been identified as fragments of fibrin (Wildenauer et al., 1991 Electrophoresis, 12:487), have also been found in elevated levels in spinal fluid from schizophrenic patients (Harrington et al., 1985 Clin. Chem., 31:722; Harrington et al., 1986 N. England. J. Med., 315:279; Wildenauer et al., 1988 Proc. Int. 2D Electroph. Conf., Verlagsgesellschaft, Vienna p. 212-218; Wildenauer et al., 1991 Electrophoresis, 12:487).
Elevated levels of other acute phase proteins are associated with CNS disorders. Altstiel et al. (1991 Amer. Coll. of Neuropsychopharm., 60) have shown an increased hepatic synthesis of .alpha..sub.1- antichymotrypsin and C reactive protein in Alzheimer's disease patients. They also describe the presence of .alpha..sub.1- antichymotrypsin and C reactive protein in the plaques of Alzheimer's disease patients' brains. These proteins can be stimulated by the cytokines interleukin-1 and interleukin-6, which are produced by reactive human astrocytes. In this regard, serum interleukin-6 has been reported as elevated in some schizophrenic patients (Shinani et al., 1991 Life Sciences, 49:661). If acute phase proteins play a role in the pathophysiology of both of these diseases, one might predict an increased incidence of Alzheimer's disease in schizophrenic patients. Prohovnik et al. (1991 Amer. Coll. of Neuropsychopharm., 67) in a review of 1,046 neuropathological records found that the prevalence of a neuropathological diagnosis consistent with Alzheimer's disease was considerably higher in schizophrenic patients than that expected for the general population.
It is an object of the present invention to define the protein variations associated with two diseases of the CNS, Alzheimer's disease and schizophrenia.